The goal of this Program Project Grant is to study neurobiological aspects of mental retardation and developmental disabilities, using clinically relevant model systems. A new theme among all components is the injury response in the central nervous system, a common feature to many pediatric disorders. All projects propose to explore factors important in development, repair and regeneration in the CNS, factors important too in the occurrence of mental retardation. Project I will investigate human arginase and arginase deficiency; Project II will investigate regulation of CNS development and of injury response; Project III will investigate transferrin gene regulation and its role in myelination and injury response; Project IV will investigate risk factors and the vulnerability of the developing brain; Project V will purify and characterize the microglia-derived myelin amplification factor and Project VI will investigate VIP and PACAP action in CNS development and injury. The investigators share: animal models, injury models, cell culture systems, cell and molecular biology approaches, and transgenic and mouse knockouts. This interactive and multidisciplinary group uses tools from molecular to cell transplant to address complex biological processes. The long term goal is to develop cell and gene therapy to restore neurobiological functions in impaired individuals. This program has recently attracted several outstanding clinical and basic scientists. This large research effort is concentrated in five closely interrelated projects. Each project is highly dependent on the expertise of investigators in the other components of the program project grant. The research efforts of the five research teams is greatly facilitated by the existence of excellent service and scientific cores in the UCLA Mental Retardation Research Center. This grant will facilitate the research training of pre- and post-doctoral fellows who wish to direct their career goals in research in mental retardation.